The role of Foxp1/2/4 mediated chromatin remodeling in skin and hair follicle dev

最近的证据表明，表观遗传状态的改变可以改变干细胞群体的能力。 分化成特定的细胞系，在某些情况下会导致去分化 将不同类型的细胞分化为更多的多能干细胞。控制这一过程的分子途径 表观遗传/染色质重塑事件仍不清楚。转录因子中的叉头或狐狸基因家族 调节因子调节组织特异性基因转录，对自我更新和 干细胞/祖细胞群体在发育过程中的分化。我们已经证明了Foxp1/2/4 狐狸因子亚家族在发育中的皮肤和毛囊中高度表达。最近的证据来自我们的 Lab和其他人证明了Foxp1/2/4和相关的FoxpS因子与染色质相互作用 包括NuRD和NCoR在内的重塑复合体抑制细胞内基因的特异性表达 差异化。我们实验室的证据表明，Foxp1/2/4与NuRD复合体的成分相互作用， 调节重要靶基因在肺和心脏中的转录抑制。我们的初步数据 提示Foxp1/2/4-NuRD相互作用对肺发育有深远的影响，如下所示 Foxp1-HDAC2和Foxp2-HDAC2复合突变小鼠的缺陷。这些研究说明了为数不多的 染色质重塑复合体NuRD与序列特异性DNA结合的例子 转录因子。鉴于Foxp1/2/4在心血管疾病的发生和发展中的这些基本作用 肺系统，我们预测它们将在调节毛囊方面起到类似的关键作用。 发展。为了探讨Foxp1/2/4在皮肤和毛囊发育中的作用，我们建议1) 通过删除表皮中的这些基因来确定Foxp1/2/4在皮肤和毛囊发育中的作用 和2)确定HDAC1/2在皮肤和毛囊发育中的作用 体内功能丧失分析。

Recent evidence has shown that alterations in epigenetic states can alter the ability of stem cell populations to differentiate into specific cell lineages and in some circumstances lead to the de-differentiation of differentiated cell types into more pluripotent stem cells. The molecular pathways controlling such epigenetic/chromatin remodeling events are still unclear. The forkhead or Fox gene family of transcriptional regulatory factors regulate tissue specific gene transcription and are important for self-renewal and differentiation of stem/progenitor cell populations during development. We have shown that the Foxp1/2/4 subfamily of Fox factors are highly expressed in developing skin and hair follicles. Recent evidence from our lab as well as others demonstrated that Foxp1/2/4 and the related FoxpS factor interact with chromatin remodeling complexes, including NuRD and NCoR to repress gene specific expression during cell differentiation. Evidence from our lab shows that Foxp1/2/4 interact with components of the NuRD complex, mediating transcriptional repression of important target genes in the lung and heart. Our preliminary data suggest that Foxp1/2/4-NuRD interactions have profound affects on lung development as demonstrated by defects in Foxp1-HDAC2 and Foxp2-HDAC2 compound mutant mice. These studies illustrate one of the few examples of the chromatin remodeling complex NuRD interacting with a sequence specific DNA binding transcription factor. Given these fundamental roles for Foxp1/2/4 in development of the cardiovascular and pulmonary systems, we predict that they will play a similarly critical role in regulation of hair follicle development. To explore the role of Foxp1/2/4 in skin and hair follicle development, we propose to 1) determine the roles for Foxp1/2/4 in skin and hair follicle development by deleting these genes in epidermal specific knockout mice and 2) Determine the roles for HDAC1/2 in skin and hair follicle development through in vivo loss of function analyses.